ABSTRACT Impulse control predicts a myriad of serious public health problems that substantially reduce life expectancy, including suicide, violence, substance use, and other risky behaviors. Although it is known that inhibitory control deficits confer risk for these clinical problems, one critical barrier to progress in this field is that much less is known about how this core regulatory process interacts with other cognitive and affective systems. Given that impulse control failures that occur in everyday life reflect the interaction of multiple cognitive and affective systems, this knowledge is critical for mapping impulse control failures onto neural circuits and accurately modeling the impulsivity that occurs in psychopathology as disruptions in neural systems. The objective of this application is to determine how functional brain networks supporting inhibitory control respond to cognitively- and affectively-challenging contexts and to evaluate the relevance of these networks for explaining clinical problems with impulsivity. We propose a novel investigation aimed at better understanding how three contexts known to challenge impulse control (cognitive resource depletion, competing appetitive cues, and negative mood induction) impact the functional brain networks that support successful inhibitory control and, ultimately, self-regulation in mental illness. First, healthy adults will undergo a thorough clinical diagnostic assessment and complete a battery of functional magnetic resonance imaging (fMRI) tasks in the MRI scanner that assess inhibitory control in different challenging contexts. These data are expected to contribute a precise working model of how functional brain networks compensate to meet the unique inhibitory control demands present in different challenging contexts. They will also add context as a level of analysis to existing neural models of inhibition, bringing them closer to capturing the multidimensional nature of inhibitory control failures in everyday life. Next, given that replication failures are common in neuroimaging research, a subset of participants will undergo a second MRI scan after a three-month period to establish the reliability of the novel functional brain metrics of inhibitory control we propose to investigate. Finally, a central goal of the NIMH RDoC initiative is to link clinical problems to neural systems (Cuthbert & Insel, 2013). Consistent with this initiative, we propose to examine disruptions in inhibitory control networks as potential transdiagnostic risk factors for externalizing disorders (e.g., alcohol/ substance use disorders, antisocial personality disorder) and as biomarkers for identifying subtypes of inhibition. This approach has the potential to create a more neuroscience-based classification of clinical problems related to impulsivity. Together, this research is expected to ultimately aid in the treatment of clinical impulsivity by leading to a deeper understanding of the brain networks that support successful inhibitory control.